Abstract Antibody responses guard the body against foreign pathogens and viral infections, and are the basis for protection elicited by vaccination. However, dysregulation of antibody responses can result in systemic autoimmunity or allergic inflammation. Therefore, the immune system has developed layers of regulation to ensure that antibody responses are potently targeted and highly controlled. Antibodies originate in the germinal center reaction, during which T follicular helper (Tfh) cells interact with germinal center B cells to produce plasma cells that produce high affinity antibody, and memory B cells which persist until antigen re- exposure. A newly discovered cell type, called a T follicular regulatory (Tfr) cell, is a specialized regulatory T cell subset that is thought to control Tfh-mediated B cell antibody responses in the germinal center. Although studies suggest Tfr cells uniquely and potently control antibody responses, the mechanisms by which this occurs are still unknown. We hypothesize that Tfr cells use specialized mechanisms to suppress antibody responses and by identifying and modulating these pathways new therapeutics can be made that 1) inhibit Tfr cells to boost antibody responses in vaccination/infection, or 2) promote Tfr cells to limit antibody in autoimmunity and allergic inflammation. The goal of this study is to use novel genetic mouse models and genomics to understand the cellular and molecular mechanisms Tfr cells use to control antibody responses in the context of model vaccination and allergic airway disease. In the first aim, we will use novel genetic models to perturb Tfr cells in the context of model vaccination and allergic inflammation to determine the precise roles of Tfr cells in modulating antibody responses. In the second aim, we will use genomic techniques, such as RNA-seq and ATAC-seq, to uncover the molecular programs used by Tfr cells to control antibody responses. Together these studies have the potential to transform our understanding of how antibody responses are regulated and will uncover new ways to modulate antibody responses in diverse disease settings.